PROJECT SUMMARY/ABSTRACT The Cancer Mechanisms (CM) Program of The Tisch Cancer Institute (TCI) is comprised of 49 members who share a common goal to catalyze basic research pertinent to cancer-relevant mechanistic discovery with the ultimate goal of generating new knowledge that will lead to improving the diagnosis, treatment, and prevention of primary cancer and systemic cancer recurrence in our unique catchment area across three key themes: 1. CELL AND NICHE BIOLOGY, 2. CELL SIGNALING NETWORKS and 3. CHROMATIN AND GENE REGULATION (see Figure 1 in the Research Strategy). Principal investigators in CM represent 15 Departments and 10 Institutes. As of February 2019, CM program members were awarded over $17 million in direct cost funding, with NCI support of $4.7 million and peer- reviewed cancer-related support of $13.7 million. In 2018, the program published 82 papers of which 22% were intra- and 17% were inter-programmatic. Our premise is that basic research focused on genetic, epigenetic, biochemical, micro-environmental, and developmental pathways that drive primary cancer initiation and maintenance, minimal residual disease, dormancy and overt metastasis, will reveal novel biomarkers and therapeutic targets to address each of these stages across both liquid and solid tumors. We aim to elucidate critical mechanisms across the three CM themes and foster intra- and inter-program collaborations in order to accelerate the transfer of discoveries into translational and clinical efforts. We will achieve this goal using orchestrated intra-programmatic efforts within CM themes (e.g. working groups, monthly meetings), and inter-programmatic collaborations with other programs such as Cancer Clinical Investigation (CCI), Cancer Prevention and Control (CPC) and Cancer Immunology (CI) or with disease focus groups such as Liver Cancer. In particular, our new strategic plan allows CM investigators, upon identifying targets, biomarkers or molecules for therapeutic intervention, to work closely with the newly created CCI program, which facilitates an accelerated translational or clinical path. Finally, our strategic plan will facilitate new collaborative research, training and education opportunities within our program and in our community (via efforts with CPC), high-impact publications, MPI/P01 submissions, clinical trials and translational output through partnership with CCI, and other team efforts that encompass CM's exceptional science.